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The effect of pancuronium pretreatment on the function of the prejunctional muscarinic receptor in guinea-pig trachea was studied by using electrical field f stimulation (EFS). The effects of cumulative doses of the muscarinic M2 receptor antagonist gallamine were investigated in tracheal smooth muscle strips from guinea-pigs after addition of pancuronium in vitro and in strips from guinea-pigs which had been pretreated with doses of pancuronium that caused 100% neuromuscular blockade. The results of both types of experiments were compared to those of control groups of the same size. In all strips a dose response curve with cumulative doses of methacholine was made before EFS was switched on. No differences were found between the mean pD2 value and slope of the concentration-response curves of untreated guinea-pigs and animals treated with anaesthetics and pancuronium. The animals showed variable responses to pancuronium. The bath concentration of pancuronium which decreased the EFSinduced contraction to half the original value varied between 14-61 pM. The intravenous dose necessary to paralyze the muscles, varied among the different guinea-pigs from 0,017 -0.085 mg*kg'1. The EFS-induced contraction for the concentration range of gallamine 0,32 pM -0.32 niM was found to differ significantly between the strips treated with pancuronium in the organ bath and their control group. For the guinea-pigs anaesthetized and pretreated with pancuronium a significant difference with control was observed at gallamine concentrations ranging from 0.032 -0.32 mM. These results show that pancuronium, added to the organ bath as well as administered intravenously to the guinea-pig, masked the inhibitory muscarinic receptor.Key Words: pancuronium, gallamine, muscarinic autoreceptor, inhibitory muscarinic receptor, tracheal smooth muscle, guinea-pig tracheaPrejunctional muscarinic autoreceptors have been demonstrated in functional and release experiments in different species like cats (1), rats (2), guinea-pigs (3-7), dogs (8) and man (4).

Characterized by the behavioral response to apomorphine, two outbred lines of Wistar rats can be recognized with constitutionally determined high (apomorphine susceptible, APO-SUS) or low (apomorphine unsusceptible, APO-UNSUS) adrenal responses to similar environmental stress. Within the accumbens nucleus, the APO-SUS and APO-UNSUS rats differ in alpha -adrenergic receptor responsiveness. This study explored whether these differences in adrenergic receptor sensitivity also exist in mesenteric resistance arteries. A Mulvany myograph was used to study the vasomotor responses of isolated mesenteric resistance arteries to adrenergic receptor stimulation. Phenylephrine (alpha1-agonist)-induced vasoconstriction did not differ between the two lines (pEC : 5.8 +/- 0.05 microM versus 5.8 +/- 0.04 microM and Emax: 36 +/- 2 kPa versus 33 +/- 1 kPa for APO-SUS, n = 9, and APO-UNSUS, n = 11, respectively, p > 0.1). After precontraction with phenylephrine, salbutamol (beta -agonist)-induced relaxation was less in APO-SUS rats (pEC50 4.9 +/- 0.06 versus 5.3 +/- 0.06M for APO-SUS, n = 9, and APO-UNSUS, n = 7, respectively, p < 0.001). Likewise, clonidine (alpha2-agonist)-induced relaxation was reduced in APO-SUS rats (pEC50: 6.7 +/- 0.07 versus 7.0 +/- 0.04, for APO-SUS, n = 9, and APO-UNSUS, n = 8, respectively; p < 0.01). In conclusion, constitutionally determined high susceptibility to stress is accompanied by an impaired vasorelaxation to adrenergic stimuli whereas vasoconstriction is unaffected. An unopposed vasoconstrictor action of norepinephrine may place the APO-SUS rats at increased risk for the development of hypertension, insulin resistance, and atherosclerosis.

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In order to investigate the consequences of stress susceptibility on vascular function, the authors assessed the respective contributions of nitric oxide (NO), prostanoids, and endothelium-derived hyperpolarizing factor to the vascular tone in rats with a constitutionally determined high and low susceptibility to behavioral stressors. In mesenteric resistance arteries mounted in a small vessel myograph and precontracted with l-phenylephrine hydrochloride (phenylephrine), the NO-synthase inhibitor N omega-nitro-l-arginine (l-NOARG, 100 microM) elicited a smaller increase of vascular tone in apomorphine-susceptible (APO-SUS) rats (P < 0.01). Addition of indomethacin (10 microM), in the presence of l-NOARG, resulted in a smaller decrease of vascular tone in APO-SUS rats (P < 0.01). Although acetylcholine-induced relaxation in phenylephrine-precontracted arteries was not different (P > 0.1), the individual components contributing to this relaxation were. In arteries precontracted with 125 mM K+, and incubated with indomethacin, acetylcholine-induced relaxation was not significantly different (pEC(50) and E(max): P > 0.1). Sensitivity (pEC(50): P < 0.05) and maximum relaxation (E(max): P < 0.001) to sodium nitroprusside, in the presence of 125 mM K+, was more pronounced in APO-SUS rats. In phenylephrine-precontracted arteries, in the presence of l-NOARG and indomethacin, maximum relaxation to ACh was reduced in APO-SUS rats (E(max): P < 0.05). This study showed that in rats with a high susceptibility to stressors, the contribution of NO to vascular tone was decreased as was the ratio of vasoconstrictor and vasodilator cyclooxygenase products in alpha-adrenergic precontracted arteries. End-organ sensitivity to NO was greater in APO-SUS rats, possibly due to up-regulation. Moreover, the contribution of endothelium-derived hyperpolarizing factor to acetylcholine-induced vasodilation was reduced in APO-SUS rat arteries.